Compound 1 is disclosed in Korean Patent Application No. 10-2006-0029138, which is incorporated herein by reference in its entirety, and exhibits superior inhibitory activity against dipeptidyl peptidase-IV (DPP IV) and thus is useful as an agent for treating diabetes. Typical examples of diseases caused by DPP IV can include, but are not limited to, diabetes, obesity, etc. Among diabetes, it is particularly useful for the treatment and prevention of type II diabetes. The term “treatment” as used above means that when the compound is used for individuals manifesting symptoms of a disease, it can interrupt or delay the progress of disease; and the term “prevention” as used above means that when the compound is used for individuals who do not manifest symptoms of a disease but have the risk of onset of disease, it can interrupt or delay the sign of disease.
The investigation of physical and chemical properties of a new drug is necessary for efficient and successful development of the new medicine. Particularly, by studying the presence of polymorphs and pseudopolymorphs of the drug and differences in physical and chemical properties between respective polymorphs the preferable crystal form of the drug can be selected in view of the pharmaceutical aspect (Remington's Pharmaceutics, Chapter 75 Preformulation); (Byrn, S. R., Solid State Chemistry of Drugs, Academic Press, New York, 1982). When the polymorphs are present in the solution, they are chemically identical, but in the solid state they respectively have definitely different X-ray diffraction patterns and exhibit differences in various physical and chemical properties. Particularly, respective polymorphs can have differences in bioavailability due to the differences in dissolution rates, and exhibit unexpected properties in the aspect of thermodynamic stability.
When a certain drug is present in the form of polymorphs, the crystal forms having different structures can be obtained depending on the conditions of recrystallization such as recrystallizing solvent, drug concentration, heating and cooling rates, temperature, stirring rate, and the like, during the procedures for preparing the drug. Therefore, in order to obtain the same crystal form a special attention is required for the management of manufacturing procedures.
Hydrates as one of pseudopolymorphs comprise a water molecule within the crystal of drug, and have a crystal form different from anhydrate. Difference in the crystal structure can be distinguished by X-ray diffraction pattern. Since in hydrates only physical properties such as crystallinity, hygroscopic property, melting point, solubility, dissolution rate, etc. are changed without any change of chemical properties providing pharmacological effects, they have a very important significance in the pharmaceutical aspect, like polymorphs (Morris, K. R. et al., Int. J. Pharm., 108, 1994, 195-206).
The knowledge which is understood up to date from various references relating to the technical field to which the present invention belongs is that there is no general tendency, for example, to prefer the hydrate to the anhydrate or vice versa, for the improvement of pharmaceutical properties including drug stability, hygroscopic property, etc. Ultimately, determination of the forms having the optimal pharmaceutical properties for respective compounds must be made by a person skilled in the relevant technical field through continuous study case by case.
Particularly, it can never be anticipated among any contemplable forms of a certain drug, i.e. free compound, salt, anhydrate and hydrate, which one can exhibit a stability with the hygroscopic property that is not changed depending on the surrounding humidity. Furthermore, among the hydrates the most stable hydration number cannot be predicted. And, even though the hydration number is the same, it is also unpredictable which crystal form would be the most stable. This is a phenomenon that is inconsistently revealed since it cannot be anticipated and belongs to the experimental area which can be confirmed only through repeated experiments.